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be essential for normal osteoclast-dependent bone resorption. Without its activity
such as in patients with the autosomal recessive disorder, pycnodysostosis (Gelb
et al.
1996
), undigested collagen fibrils were found to accumulate in lysosomes
within the osteoclast (Everts et al.
2003
).
The role of cathepsin K as the critical bone-degrading protease became apparent
when it was noted that, unlike MMPs which cleave collagen creating typical 1/4 C-
terminal and 3/4 N-terminal fragments, cathepsin K can cleave collagen at multiple
locations resulting in a more complete degradation (Garnero et al.
1998
; Kafienah et al.
1998
). MMPs had previously been suggested to play a role in bone degradation;
however, MMPs expressed by osteoclasts are nowconsidered to play amore regulatory
role governing migration and the initiation of resorption (Engsig et al.
2000
; Holliday
et al.
1997
; Parikka et al.
2001
;Satoetal.
1998
). It should be noted that in calvarial
bone, collagenolytic MMPs may play a greater role in collagen digestion (Everts et al.
1999
). Figure
2.4
depicts the action of cathepsin K in osteoclastic bone resorption.
The ability of cathepsin K to degrade type I collagen and elastin more effectively
than other collagenolytic or elastolytic enzymes (Br
omme et al.
1996
; Garnero et al.
1998
; Kafienah et al.
1998
) has led to many investigations into its inhibition for
pathological conditions. Collagen fragments created by cathepsin K can be detected
€
Fig. 2.4 Schematic representation of bone resorbing osteoclasts. (a) The secretion of active
cathepsin K into the resorption lacuna where the degradation of type I collagen occurs. Endocy-
tosed collagen fibrils are rapidly degraded intracellularly. Digested collagen fragments can be
transcytosed through the cell and released on the apical site of the cell. (b) A cathepsin K-deficient
osteoclast which is unable to degrade the bone collagen matrix. As a consequence, endocytosed
collagen fibrils accumulate within the cell. However, the cell remains capable to demineralize the
bone matrix using the vATPase system
